Stressed podocytes—mechanical forces, sensors, signaling and response

Abstract

Increased glomerular capillary pressure (glomerular hypertension) and increased glomerular filtration rate (glomerular hyperfiltration) have been proven to cause glomerulosclerosis in animal models and are likely to be operative in patients. Since podocytes cover the glomerular basement membrane, they are exposed to tensile stress due to circumferential wall tension and to fluid shear stress arising from filtrate flow through the narrow filtration slits and through Bowman's space. In vitro evidence documents that podocytes respond to tensile stress as well as to fluid shear stress. Several proteins are discussed in this review that are expressed in podocytes and could act as mechanosensors converting mechanical force via a conformational change into a biochemical signal. The cation channels P2X4 and TRPC6 were shown to be involved in mechanosignaling in podocytes. P2X4 is activated by stretch-induced ATP release, while TRPC6 might be inherently mechanosensitive. Membrane, slit diaphragm and cell-matrix contact proteins are connected to the sublemmal actin network in podocytes via various linker proteins. Therefore, actin-associated proteins, like the proven mechanosensor filamin, are ideal candidates to sense forces in the podocyte cytoskeleton. Furthermore, podocytes express talin, p130Cas, and fibronectin that are known to undergo a conformational change in response to mechanical force exposing cryptic binding sites. Downstream of mechanosensors, experimental evidence suggests the involvement of MAP kinases, Ca and COX2 in mechanosignaling and an emerging role of YAP/TAZ. In summary, our understanding of mechanotransduction in podocytes is still sketchy, but future progress holds promise to identify targets to alleviate conditions of increased mechanical load.

Single kidney transplantation from donors with acute kidney injury: A single‐center experience

“…Foss et al, reported similar results and stated that kidneys from pediatric donors continued to grow until they did not significantly differ from the adult kidney size at 1 year post‐transplant. An increased glomerular capillary pressure and GFR have been proven to be related to the tensile stress of podocytes and the GBM . We hypothesized that the growth of pediatric kidneys may have alleviated injury by repairing the podocytes and GBM; hence, the proteinuria decreased and the renal function recovered as the allograft grew, even though the pediatric donors had AKI, and this could be certified by our results of similar renal size ( P = 0.094), proteinuria ( P = 0.271), and eGFR ( P = 0.196) at six months post‐transplant.…”

“…An increased glomerular capillary pressure and GFR have been proven to be related to the tensile stress of podocytes and the GBM. 31 We F I G U R E 2 Comparison of outcomes in recipients with different age and AKI status donors (pediatric AKI, pediatric non-AKI, adult AKI, adult non-AKI). A, SCr levels; B, eGFR; C, proteinuria, and D, renal size.…”

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

“…We find histamine, muscarinic, and endothelin receptor responses unaffected by substrate stiffness; hence, they do not respond to the kind of mechanical stress required for OGR1 activation. Many cell types, including endothelia, osteoblasts, podocytes, and stem cells, respond differently to shear and stretch stress [22][23][24][25], suggesting that these two different mechanical stimuli activate different intracellular signaling pathways. Hence, shear and stretch forces can be recognized as distinct events by cells that experience them.…”

Protein half‐life determines expression of proteostatic networks in podocyte differentiation

“…However, certain limitations are important when interpreting results from cultured podocyte cell lines: immortalized podocytes are usually cultivated in petri dishes as single cells and not in a 3-dimensional space with mesangial and endothelial cells in proximity. Moreover, podocytes in culture do not commonly face the mechanical stretch and the flow of primary urine filtrate as podocytes in vivo (6). In culture, podocytes do not form secondary processes with slit diaphragms in between neighboring ABBREVIATIONS: 2D, 2-dimensional; ACTN4, a-actinin-4; ANLN, anillin; ARHGDIA, r-GDP-dissociation inhibitor a; BM, basement membrane; BNIP3, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; BNIP3L, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; BSA, bovine serum albumin; CBX1, chromobox protein homolog 1; CD2AP, CD2-associated protein; CD80, T lymphocyte-activation antigen CD80; CHX, cycloheximide; CNN1, calponin-1; COBLL1, cordon-bleu protein-like 1; CTSD, cathepsin D; DAPK1/3, death-associated protein kinase 1; DAPK3, death-associated protein kinase 3; DQ-BSA, dequenched bovine serum albumin; ER, endoplasmic reticulum; ESI, electrospray ionization; FA, formic acid; F-actin, filamentous actin; FBS, fetal bovine serum; FDR, false-discovery rate; FPKM, fragments per kilobase million; FSGS, focal segmental glomerulosclerosis; GO, gene ontology; GO-CC, gene ontology cellular component; GSN, gelsolin; iBAQ, intensity-based absolute quantification; ITGA3, integrin a-3; LAMB2, laminin subunit b-2; LAMP1/2, lysosomal-associated membrane protein 1/2; LFQ, label-free quantification; LMNA, lamin A/C; MS/MS, tandem mass spectrometry; MYH9, myosin-9; NCK1/2, cytoplasmic protein NCK1/2; nLC, nano liquid chromatography; pSILAC, pulsed stable isotope labeling by amino acids in cell culture; PSM, peptide spectrum match; RBBP4, retinoblastoma-binding protein 4; RPMI, Roswell Park Memorial Institute; SYNPO, synaptopodin; t 1/2 , half-life; TRPC6, short transient receptor potential cation channel 6; WT1, Wilms tumor protein 1 cells.…”